Patients with schizophrenia (SCH) commonly develop alcohol use disorders. While typical antipsychotic drugs (e.g., haloperidol - HAL) do not control alcohol use in these patients, recent data suggest that the atypical antipsychotic clozapine (CLOZ) does. We recently presented a neurobiologic formulation suggesting: (a) that persons with SCH have a dysfunction in their dopamine (DA) mediated mesocorticolimbic reward pathways underlying alcohol use; (b) that most antipsychotic drugs (e.g., HAL) do not decrease alcohol use in this population because they do not restore the normal function of these pathways; but (c) that CLOZ, through its actions on multiple neurotransmitter systems, particularly its potent blockade of alpha 2 noradrenergic receptors, as well as its weak blockade of DA D2 receptors, has a normalizing effect on the signal detection capability of these pathways. To further elucidate the differential effects of HAL and CLOZ, we recently initiated a study in Syrian golden hamsters, an outbred animal that drinks large amounts of alcohol. Our initial data indicate that CLOZ but not HAL substantially decreases hamster alcohol drinking. In this R03 proposal, we seek to expand our investigations and prepare for submission of an R01 proposal. We will continue studies of the hamster, but will also expand to include the "P" rat, a genetically- bred strain that has been proposed as an excellent animal model for alcoholism. Our overarching hypothesis is that CLOZ's effect in alcohol-preferring animals, as in patients with SCH and comorbid alcohol use disorder, relates to its action in DA-mediated mesolimbic circuits. The primary specific aim seeks: (1) To determine whether CLOZ will decrease alcohol drinking more than HAL does in the P rat, a rodent with known dysfunction in the DA-mediated mesolimbic system. The other aims are designed to further inform the neurobiologic basis by which CLOZ, but not HAL, limits alcohol use in the hamster and, potentially, in the P rat: (2) To explore whether loss of suppression of alcohol drinking develops during long-term treatment with CLOZ; and (3) to begin to explore (a) whether addition of a potent D2 antagonist to CLOZ will lessen the CLOZ's ability to suppress alcohol drinking, and (b) whether addition of a potent alpha 2 antagonist to HAL will allow HAL to suppress alcohol drinking. The long-term goal of our research is to create better treatments for alcoholism in patients with SCH (and possibly even in those without SCH). [unreadable] [unreadable]